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ATF6α activation in human and preclinical models of hepatocellular carcinoma is significantly associated with an aggressive tumour phenotype characterized by reduced survival, glycolytic reprogramming and local immunosuppression.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

The lowest-frequency gravitational wave background may be shaped by supermassive black hole binaries that scatter nearby stars or dark matter. In this case, the NANOGrav 15-year dataset favours dense galactic centres with 10⁶ solar masses per cubic parsec.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Leidal et al. show that the LC3-conjugation pathway, which is part of the autophagy machinery, controls extracellular vesicle cargo loading and secretion of RNA-binding proteins.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Sediments accumulated in a subduction trench are usually unconsolidated and impede the updip propagation of fault rupture during an earthquake. Seismic images of the southern Sumatra–Andaman trench reveal blocks of consolidated sediment that may have enabled fault rupture in 2004 to propagate up fault dip, thus further seaward, increasing the tsunami magnitude.

Over the past 18,000 years, the residence time and amount of soil carbon stored in the Ganges–Brahmaputra basin have been controlled by the intensity of Indian Summer Monsoon rainfall, with greater carbon destabilization during wetter, warmer conditions.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

The existing ENCODE registry of candidate human and mouse cis-regulatory elements is expanded with the addition of new ENCODE data, integrating new functional data as well as new cell and tissue types.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

During the early to mid-Holocene, Africa was more humid than today. Precipitation reconstructions from across Africa suggest that the termination of humidity was spatially variable, moving towards progressively lower latitudes.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

Many tumours exhibit hypoxia (low oxygen) and hypoxic tumours often respond poorly to therapy. Here, the authors quantify hypoxia in 1188 tumours from 27 cancer types, showing elevated hypoxia links to increased mutational load, directing evolutionary trajectories.

Amyloid plaques are a hallmark of Alzheimer’s disease. Better understanding of their biochemistry can inspire new biomarkers and therapeutics. Using multimodal mass spectrometry imaging, this work reveals surprising lipid heterogeneity in plaque microenvironments across the brain.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

Starting from zero knowledge and without human data, AlphaGo Zero was able to teach itself to play Go and to develop novel strategies that provide new insights into the oldest of games.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

A computer Go program based on deep neural networks defeats a human professional player to achieve one of the grand challenges of artificial intelligence.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Cancers evolve as they progress under differing selective pressures. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, the authors present the method TrackSig the estimates evolutionary trajectories of somatic mutational processes from single bulk tumour data.

Flies navigate to food sources by combining odour and wind-direction cues. This study identifies pathways to the fan-shaped body that encode these signals, and demonstrates how local neurons integrate odour- and wind information to guide navigation.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

Our understanding of the genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. Here, the authors impute whole-body imaging adiposity phenotypes in large biobanks, enhancing their power to discover genes driving human adiposity, and further investigate one such gene using a mouse model.

Current knowledge on the genetic basis of the human face is incomplete. By performing a combined GWAS of almost 1,000 facial traits, the authors enhance the genetic understanding of human facial variation and improve genetic face prediction.

Wood density is a key control on tree biomass, and understanding its spatial variation improves estimates of forest carbon stock. Sullivan et al. measure >900 forest plots to quantify wood density and produce high resolution maps of its variation across South American tropical forests.

Safely opening university campuses has been a major challenge during the COVID-19 pandemic. Here, the authors describe a program of public health measures employed at a university in the United States which, combined with other non-pharmaceutical interventions, allowed the university to stay open in fall 2020 with limited evidence of transmission.

Here, the authors identify a copy number variation containing three enhancers (PIHEC) that drives bilateral constricted ear by co-ordinately regulating HMX1 expression, revealing how aberrant Hmx1 expression in neural crest-derived fibroblasts disrupts outer ear development.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.